Pulmonary hypertension (PH) has several aetiologies, including lung diseases and/or hypoxia, which, in fact, are among the most common conditions underlying an increase in pulmonary artery pressure (PAP) and are clustered together in the current classification of PH.1 Sleep-disordered breathing is listed within this group, based on the clinical experience and scientific evidence that obstructive sleep apnoea syndrome (OSAS) and PH may coexist.2 However, it is unclear whether OSAS in itself causes PH. In rodents, intermittent hypoxia leads to PH, increased right ventricular (RV) systolic pressure and RV hypertrophy in a few weeks, with the underlying mechanism being hypoxia-driven small pulmonary artery constriction and remodelling.3 These events are assumed to occur also in OSAS, but animal data may be not transposable to humans, because of differences in the patterns of the episodes of hypoxia and in the responses to them between experimental models and patients. Most importantly, OSAS has an extremely complex pathogenesis and it is frequently associated with other diseases that may trigger PH. OSAS is often observed in patients with chronic obstructive pulmonary disease,4 as well as with subclinical or overt cardiovascular disease, especially atrial fibrillation and heart failure.5 In this context, it is difficult to discriminate whether an increase in PAP results from obstructive sleep apnoea, concomitant pulmonary disease and/or ventilation impairment, or the backward transmission of elevated filling pressures of the left cardiac chambers. Clinically, all these conditions may present with dyspnoea and the differential diagnosis may be challenging.6
PH is suspected on the basis of transthoracic echocardiography, but must be confirmed by right heart catheterisation (RHC). In earlier investigations with RHC, a substantial proportion of cases were found to have high pulmonary artery wedge pressures,7,,–10 indicating that PH in OSAS is indeed not uncommonly due to left-sided heart disease.
Current guidelines for PH recommend that RHC follows the exclusion of lung and left heart disease, and the echocardiographic demonstration of a peak tricuspid regurgitation velocity (TRV) of 2.9 m/s or greater or other signs of PH.1 Thus, we devised a pragmatic study in which treatment-naive patients with severe OSAS and no evidence of concomitant pulmonary or cardiac disease were prospectively selected and evaluated by the 6-minute walking test, measurement of N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration and arterial blood gases; moreover, echocardiography was performed. Those with a suspicion of PH on non-invasive testing were scheduled for RHC. We focused on subjects with severe OSAS based on the reasoning that they are more likely to have both PH and heart and lung abnormalities and, thus, they represent a subgroup for which the diagnostic work-up proposed by the guidelines may be especially important.
Schematic diagram of the study design and results. The text summarises the defining characteristics and the size of the patient subgroups, as sequentially identified. OSAS: obstructive sleep apnoea syndrome; RHC: right heart catheterisation.
Characteristics of the patients evaluated in the study.
| Group A | Group B | Group C | Group D | Group E | |
|---|---|---|---|---|---|
| Cardiac/lung disease | Yes | No | No | No | No |
| AHI | Any | Any | <30 | ≥30 | ≥30 |
| Spirometry | – | – | Any | Any | Normal |
| N | 84 | 121 | 81 | 40 | 30 |
| Age (years) | 66.1 ± 10.3 | 55.6 ± 13.4** | 53.6 ± 14.1 | 59.7 ± 10.8# | 59.7 ± 11.4 |
| Men | 51 (60.8%) | 82 (67.8%) | 53 (65.4%) | 29 (72.5%) | 23 (76.7%) |
| AHI | 32.2 (15.9–46.6) | 19.6 (10.6–38.6)** | 13 (8.7–19.7) | 51.7 (38.1–65.6)## | 45.2 (34.2–58.5) |
| Sleep SpO2 (%) | 92 (90–93) | 94 (92–95)** | 94 (93–95) | 92 (90–94)## | 92 (91–94) |
| T90 (%) | 13.5 (4–26) | 2 (0–11)** | 0 (0–3) | 11 (4–31.5)## | 11 (4–21) |
| Desaturation index | 33.1 (20.3–51) | 24.4 (12.4–40.7)** | 16.9 (9.3–24.6) | 54.5 (39–74.1)## | 50.3 (38.7–68.1) |
| FEV1/FVC | – | – | – | 76.5 ± 6.9 | 79 ± 4.8 |
| TLC (L) | – | – | – | 96 ± 18.3 | 97.4 ± 10.8 |
| PaO2 (mmHg) | – | – | – | 82.8 ± 10.3 | 83.8 ± 9.9 |
| PaCO2 (mmHg) | – | – | – | 38.3 ± 2.6 | 38.3 ± 2.6 |
| LVEDVi (mL/m2) | – | – | – | – | 51.1 ± 11.4 |
| LVEF (%) | – | – | – | – | 61.2 ± 4.3 |
| E/A | – | – | – | – | 0.9 ± 0.2 |
| E/E′ | 6.4 ± 2.1 | ||||
| LAi (cm2/m2) | – | – | – | – | 9.7 ± 2.5 |
| RVOT (mm) | – | – | – | – | 28 ± 4 |
| TAPSE (mm) | – | – | – | – | 24.9 ± 3.4 |
| RAi (cm2/m2) | – | – | – | – | 8 ± 1.7 |
| PAT (m/s) | – | – | – | – | 128.1 ± 23.2 |
| RV/LV | – | – | – | – | 0.7 ± 0.1 |
| Group A | Group B | Group C | Group D | Group E | |
|---|---|---|---|---|---|
| Cardiac/lung disease | Yes | No | No | No | No |
| AHI | Any | Any | <30 | ≥30 | ≥30 |
| Spirometry | – | – | Any | Any | Normal |
| N | 84 | 121 | 81 | 40 | 30 |
| Age (years) | 66.1 ± 10.3 | 55.6 ± 13.4** | 53.6 ± 14.1 | 59.7 ± 10.8# | 59.7 ± 11.4 |
| Men | 51 (60.8%) | 82 (67.8%) | 53 (65.4%) | 29 (72.5%) | 23 (76.7%) |
| AHI | 32.2 (15.9–46.6) | 19.6 (10.6–38.6)** | 13 (8.7–19.7) | 51.7 (38.1–65.6)## | 45.2 (34.2–58.5) |
| Sleep SpO2 (%) | 92 (90–93) | 94 (92–95)** | 94 (93–95) | 92 (90–94)## | 92 (91–94) |
| T90 (%) | 13.5 (4–26) | 2 (0–11)** | 0 (0–3) | 11 (4–31.5)## | 11 (4–21) |
| Desaturation index | 33.1 (20.3–51) | 24.4 (12.4–40.7)** | 16.9 (9.3–24.6) | 54.5 (39–74.1)## | 50.3 (38.7–68.1) |
| FEV1/FVC | – | – | – | 76.5 ± 6.9 | 79 ± 4.8 |
| TLC (L) | – | – | – | 96 ± 18.3 | 97.4 ± 10.8 |
| PaO2 (mmHg) | – | – | – | 82.8 ± 10.3 | 83.8 ± 9.9 |
| PaCO2 (mmHg) | – | – | – | 38.3 ± 2.6 | 38.3 ± 2.6 |
| LVEDVi (mL/m2) | – | – | – | – | 51.1 ± 11.4 |
| LVEF (%) | – | – | – | – | 61.2 ± 4.3 |
| E/A | – | – | – | – | 0.9 ± 0.2 |
| E/E′ | 6.4 ± 2.1 | ||||
| LAi (cm2/m2) | – | – | – | – | 9.7 ± 2.5 |
| RVOT (mm) | – | – | – | – | 28 ± 4 |
| TAPSE (mm) | – | – | – | – | 24.9 ± 3.4 |
| RAi (cm2/m2) | – | – | – | – | 8 ± 1.7 |
| PAT (m/s) | – | – | – | – | 128.1 ± 23.2 |
| RV/LV | – | – | – | – | 0.7 ± 0.1 |
Categorical data are presented as the number of observations (% of total) and continuous data as mean ± SD or median (interquartile range), depending on the distribution.
Comparisons were drawn using the chi-square test, unpaired t test or Mann–Whitney test, as appropriate.
**P < 0.01 vs. group A; # and ##P < 0.05 and P < 0.01 vs. group C, respectively.
AHI apnoea–hypopnoea index; SpO2 sleep time oxygen saturation by pulse oximetry; T90: percentage sleep time with oxygen saturation of 90% or less; FEV1/FVC: ratio between forced expiratory volume during the first second and forced vital capacity; TLC: total lung capacity; PaO2: arterial partial pressure of oxygen; PaCO2: arterial partial pressure of carbon dioxide; LVEDVi: left ventricular end-diastolic volume indexed to body surface area; LVEF: left ventricular ejection fraction; E/A: ratio between early mitral inflow velocity (E wave) and peak velocity flow in late diastole (A wave); E/E′: ratio between E wave and mitral annular early diastolic velocity; Lai: left atrium indexed to body surface area; RVOT: right ventricular outflow tract; TAPSE: tricuspid annular plane systolic excursion; RAi: right atrium indexed to body surface area; PAT: pulmonary acceleration time; RV/LV: right ventricle/left ventricle basal diameter ratio.
Characteristics of the patients evaluated in the study.
| Group A | Group B | Group C | Group D | Group E | |
|---|---|---|---|---|---|
| Cardiac/lung disease | Yes | No | No | No | No |
| AHI | Any | Any | <30 | ≥30 | ≥30 |
| Spirometry | – | – | Any | Any | Normal |
| N | 84 | 121 | 81 | 40 | 30 |
| Age (years) | 66.1 ± 10.3 | 55.6 ± 13.4** | 53.6 ± 14.1 | 59.7 ± 10.8# | 59.7 ± 11.4 |
| Men | 51 (60.8%) | 82 (67.8%) | 53 (65.4%) | 29 (72.5%) | 23 (76.7%) |
| AHI | 32.2 (15.9–46.6) | 19.6 (10.6–38.6)** | 13 (8.7–19.7) | 51.7 (38.1–65.6)## | 45.2 (34.2–58.5) |
| Sleep SpO2 (%) | 92 (90–93) | 94 (92–95)** | 94 (93–95) | 92 (90–94)## | 92 (91–94) |
| T90 (%) | 13.5 (4–26) | 2 (0–11)** | 0 (0–3) | 11 (4–31.5)## | 11 (4–21) |
| Desaturation index | 33.1 (20.3–51) | 24.4 (12.4–40.7)** | 16.9 (9.3–24.6) | 54.5 (39–74.1)## | 50.3 (38.7–68.1) |
| FEV1/FVC | – | – | – | 76.5 ± 6.9 | 79 ± 4.8 |
| TLC (L) | – | – | – | 96 ± 18.3 | 97.4 ± 10.8 |
| PaO2 (mmHg) | – | – | – | 82.8 ± 10.3 | 83.8 ± 9.9 |
| PaCO2 (mmHg) | – | – | – | 38.3 ± 2.6 | 38.3 ± 2.6 |
| LVEDVi (mL/m2) | – | – | – | – | 51.1 ± 11.4 |
| LVEF (%) | – | – | – | – | 61.2 ± 4.3 |
| E/A | – | – | – | – | 0.9 ± 0.2 |
| E/E′ | 6.4 ± 2.1 | ||||
| LAi (cm2/m2) | – | – | – | – | 9.7 ± 2.5 |
| RVOT (mm) | – | – | – | – | 28 ± 4 |
| TAPSE (mm) | – | – | – | – | 24.9 ± 3.4 |
| RAi (cm2/m2) | – | – | – | – | 8 ± 1.7 |
| PAT (m/s) | – | – | – | – | 128.1 ± 23.2 |
| RV/LV | – | – | – | – | 0.7 ± 0.1 |
| Group A | Group B | Group C | Group D | Group E | |
|---|---|---|---|---|---|
| Cardiac/lung disease | Yes | No | No | No | No |
| AHI | Any | Any | <30 | ≥30 | ≥30 |
| Spirometry | – | – | Any | Any | Normal |
| N | 84 | 121 | 81 | 40 | 30 |
| Age (years) | 66.1 ± 10.3 | 55.6 ± 13.4** | 53.6 ± 14.1 | 59.7 ± 10.8# | 59.7 ± 11.4 |
| Men | 51 (60.8%) | 82 (67.8%) | 53 (65.4%) | 29 (72.5%) | 23 (76.7%) |
| AHI | 32.2 (15.9–46.6) | 19.6 (10.6–38.6)** | 13 (8.7–19.7) | 51.7 (38.1–65.6)## | 45.2 (34.2–58.5) |
| Sleep SpO2 (%) | 92 (90–93) | 94 (92–95)** | 94 (93–95) | 92 (90–94)## | 92 (91–94) |
| T90 (%) | 13.5 (4–26) | 2 (0–11)** | 0 (0–3) | 11 (4–31.5)## | 11 (4–21) |
| Desaturation index | 33.1 (20.3–51) | 24.4 (12.4–40.7)** | 16.9 (9.3–24.6) | 54.5 (39–74.1)## | 50.3 (38.7–68.1) |
| FEV1/FVC | – | – | – | 76.5 ± 6.9 | 79 ± 4.8 |
| TLC (L) | – | – | – | 96 ± 18.3 | 97.4 ± 10.8 |
| PaO2 (mmHg) | – | – | – | 82.8 ± 10.3 | 83.8 ± 9.9 |
| PaCO2 (mmHg) | – | – | – | 38.3 ± 2.6 | 38.3 ± 2.6 |
| LVEDVi (mL/m2) | – | – | – | – | 51.1 ± 11.4 |
| LVEF (%) | – | – | – | – | 61.2 ± 4.3 |
| E/A | – | – | – | – | 0.9 ± 0.2 |
| E/E′ | 6.4 ± 2.1 | ||||
| LAi (cm2/m2) | – | – | – | – | 9.7 ± 2.5 |
| RVOT (mm) | – | – | – | – | 28 ± 4 |
| TAPSE (mm) | – | – | – | – | 24.9 ± 3.4 |
| RAi (cm2/m2) | – | – | – | – | 8 ± 1.7 |
| PAT (m/s) | – | – | – | – | 128.1 ± 23.2 |
| RV/LV | – | – | – | – | 0.7 ± 0.1 |
Categorical data are presented as the number of observations (% of total) and continuous data as mean ± SD or median (interquartile range), depending on the distribution.
Comparisons were drawn using the chi-square test, unpaired t test or Mann–Whitney test, as appropriate.
**P < 0.01 vs. group A; # and ##P < 0.05 and P < 0.01 vs. group C, respectively.
AHI apnoea–hypopnoea index; SpO2 sleep time oxygen saturation by pulse oximetry; T90: percentage sleep time with oxygen saturation of 90% or less; FEV1/FVC: ratio between forced expiratory volume during the first second and forced vital capacity; TLC: total lung capacity; PaO2: arterial partial pressure of oxygen; PaCO2: arterial partial pressure of carbon dioxide; LVEDVi: left ventricular end-diastolic volume indexed to body surface area; LVEF: left ventricular ejection fraction; E/A: ratio between early mitral inflow velocity (E wave) and peak velocity flow in late diastole (A wave); E/E′: ratio between E wave and mitral annular early diastolic velocity; Lai: left atrium indexed to body surface area; RVOT: right ventricular outflow tract; TAPSE: tricuspid annular plane systolic excursion; RAi: right atrium indexed to body surface area; PAT: pulmonary acceleration time; RV/LV: right ventricle/left ventricle basal diameter ratio.
To exclude an unknown pulmonary disease, the patients in group D were studied by spirometry/plethysmography: 30 (14.6% of total, group E) did not have significant obstructive or restrictive lung function impairment, i.e. ratio between forced expiratory volume during the first second and forced vital capacity (FEV1/FVC) less than 70 and total lung capacity less than 70 L, and were investigated further (Figure 1). Their body mass index (BMI) was 31.1 ± 5.4 kg/m2 and the mean 6-minute walk test distance was 436 ± 70 m. None had symptoms or signs of PH or RV failure, nor abnormal NT-proBNP (median 18 (interquartile range 13–29.1) pg/mL, upper normal limit of 125 pg/mL). No tricuspid regurgitation was detectable by echocardiography in five cases and peak TRV was less than 2.9 m/s in the others (mean 2.35 ± 0.3 m/s). RV size and function, right atrial area and pulmonary acceleration time, which may be altered because of PH,1 were also normal, as were left chamber dimensions and function (Table 1). The inferior vena cava was non-dilated and always collapsible at visual assessment. Moreover, no clinically relevant valve alterations were found.
Hence, by following a guideline-recommended approach we did not identify any case of possible PH that would support RHC in a contemporary series of patients with severe OSAS. The limitations of this study include the small number of patients examined, the exclusion of non-severe OSAS, and the possibility that PH-related vascular changes had either not yet occurred or were present in the absence of symptoms or echocardiographic alterations. The small sample also did not allow us to assess the role of raised BMI, which was previously reported to mediate the association of PH with OSAS.7 In fact, the mean BMI was high in our cohort and it is conceivable that extensive cardiovascular assessment would have revealed some degree of abnormality. Therefore, the present work does not answer the question of whether, how and to what extent isolated sleep-disordered breathing may be an independent cause of PH. On the other hand, our results support the conclusion that patients with OSAS must be primarily and carefully screened for concomitant lung and/or heart disease, rather than for PH.
RM, DC, RS and MB contributed to the acquisition, analysis and interpretation of data for the work and critically revised the manuscript. FB contributed to the conception of the work and critically revised the manuscript. PA conceived and designed the work and drafted the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work ensuring integrity and accuracy.
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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